Initial testing of the 2009 pandemic influenza A (H1N1) virus found it susceptible to neuraminidase inhibitors (oseltamivir and zanamivir) and resistant to adamantanes (amantadine and rimantadine) (1). Neuraminidase inhibitors have been used widely for treatment and chemoprophylaxis of 2009 pandemic influenza A (H1N1); however, sporadic cases of oseltamivir-resistant 2009 pandemic influenza A (H1N1) virus infection have been reported worldwide (2), including nine U.S. cases identified as of September 4.* On July 14, CDC was contacted by a physician at a summer camp in North Carolina regarding two cases of influenza-like illness (ILI) in adolescent girls receiving oseltamivir chemoprophylaxis during an ILI outbreak that had begun June 18. The two girls stayed in the same cabin, and both received oseltamivir during a mass chemoprophylaxis program in which approximately 600 campers and staff members received oseltamivir or zanamivir. On July 20 and July 22, the North Carolina State Laboratory of Public Health confirmed pandemic H1N1 virus infection in respiratory specimens from both girls. On August 14 and August 19, CDC detected the H275Y mutation (N1 numbering) in neuraminidase from both specimens by pyrosequencing (3,4). The H275Y mutation is associated with resistance to oseltamivir; zanamivir susceptibility is retained. A second mutation (I223V) in neuraminidase also was detected in both specimens. This is the first report of oseltamivir resistance in pandemic H1N1 cases with an epidemiologic link. Health-care providers should be aware that antiviral resistance can develop during chemoprophylaxis or treatment with subtherapeutic dosages and should follow published recommendations for antiviral medications (5).
The summer camp offered two 4-week sessions. The first session was conducted from June 14 to July 10, followed by a weekend break, July 11--12, before the start of the second session on July 13. Approximately 650 campers and 350 staff members participated in the first session, and 350 campers and 300 staff members participated in the second session. An outbreak of ILI began on June 18, soon after the start of the first session; the last case was diagnosed on July 22. All ill persons were grouped in isolation until 7 days after symptom onset and until well. All but one of the 61 ill campers and four ill staff members received treatment with either oseltamivir or zanamivir. Also, beginning on June 18, medical staff members conducted a mass program of antiviral chemoprophylaxis in which prophylactic oseltamivir or zanamivir was administered to all persons who had an ill sibling at the camp and to all persons who lived in a cabin with an ill person. Chemoprophylaxis was administered daily by camp staff members to ensure compliance. Over the two sessions, a total of 418 campers and 189 staff members received 10 days of chemoprophylaxis with either oseltamivir (75 mg or appropriate weight-based dosing, once daily) or zanamivir (two 5 mg inhalations, once daily). The camp medical staff continued the program until July 24.
Case Reports
Patient A. One of the campers, a previously healthy adolescent girl, received oseltamivir prophylaxis at an appropriate prophylactic dose of 75 mg daily during June 26--July 5, despite having no reported exposure to an ill person. After completing the initial course of oseltamivir on July 5, she was exposed to an ill cabin mate (patient C) and administered a second 10-day course of chemoprophylaxis at the same dosage beginning on July 7. On July 8, she experienced cough and headache without fever, and on July 9 she experienced chills, worsening headache, and loose stools. Despite these symptoms, her oseltamivir dose was not increased to a therapeutic treatment dose. On July 10, the last day of the first camp session, she traveled away from camp with three family members while ill, returning on July 12, afebrile and with a cough, to attend the second session. On July 12, a rapid influenza detection test was positive for influenza A. The family declined treatment with zanamivir because of concern over side effects, and the patient's oseltamivir dose was doubled to 75 mg, twice daily, an appropriate therapeutic treatment dose. Patient A was isolated with other ill campers and staff members until July 16, and she recovered uneventfully. The camp physician observed that the camper became ill while taking prophylaxis and became concerned that antiviral resistance might have occurred. Therefore, a nasopharyngeal swab specimen was obtained on July 14 and sent to the state laboratory for testing. On July 22, the laboratory confirmed the presence of 2009 pandemic influenza A (H1N1) virus by real-time reverse transcription--polymerase chain reaction (rRT-PCR). On August 19, CDC testing of the same clinical specimen detected the H275Y (3,4) and I223V mutations (6). Because viral isolation was unsuccessful, a neuraminidase inhibition assay was not performed. No illness was reported among her family members.
Patient B. A second previously healthy adolescent girl, who resided in the same cabin as patient A, began oseltamivir chemoprophylaxis at a dose of 75 mg daily on July 7 after exposure to patient C. On July 10, patient B left camp for a home visit during the break between camp sessions. The next day, while at home, she experienced onset of fever (101.9ºF [38.8ºC]), sore throat, and cough. She continued to engage in normal activities while ill, including visiting a shopping mall and movie theater. She returned to camp for the second session on July 12 with fever, headache, cough, malaise, and myalgias. On July 12, a rapid influenza detection test was positive for influenza A. Oseltamivir was discontinued, and zanamivir treatment (two 5 mg inhalations, twice daily) was begun. A nasopharyngeal swab specimen was obtained July 14 and sent to the state laboratory for testing. On July 20, the presence of 2009 pandemic influenza A (H1N1) virus was confirmed by rRT-PCR. On August 14, CDC testing of viral RNA detected H275Y and I223V mutations (3,4,6). Viral isolation was unsuccessful, and a neuraminidase inhibition assay was not performed. Patient B was isolated at the camp during July 12--18. Her fever resolved by July 14, and by July 17 she was asymptomatic. No illnesses were identified among close contacts potentially exposed during her weekend home visit.
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Source: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5835a1.htm 
